title: Acute DPP-4 inhibition modulates vascular tone through GLP-1 independent pathways.
abstract: Evidence from both clinical and experimental studies indicates that Di-peptidyl peptidase-IV (DPP-4) inhibition may mediate favorable effects on the cardiovascular system. The objective of this study was to examine the acute effects of DPP-4 inhibition on vascular responses and to study the underlying mechanisms of alteration in tone. Aortic segments from C57BL/6 mice were treated with vasoconstrictors and exposed to various doses of alogliptin, a selective DPP-4 inhibitor. Vasodilator responses were evaluated using pathway specific antagonists to elucidate mechanisms of response. In parallel experiments, cultured human umbilical vein endothelial cells (HUVEC) were exposed to varying concentrations of alogliptin to evaluate the effects on candidate vasodilator pathways. Alogliptin relaxed phenylephrine and U46619 pre-constricted aortic segments in a dose dependent manner. Relaxation responses were not affected by the glucagon-like peptide-1 (GLP-1) receptor antagonist, exendin fragment 9-39 (88 ± 6 vs. 91 ± 2, p < 0.001). Vascular relaxation to alogliptin was significantly decreased by endothelial denudation, L-N(G)-monomethyl-arginine citrate (L-NMMA) and by the soluble guanylate cyclase inhibitor ODQ. DPP-4 inhibition induced relaxation was completely abolished by a combination of L-NMMA, charybdotoxin and apamin. Incubation of HUVECs with alogliptin resulted in eNOS and Akt phosphorylation (Ser(1177) and Ser(473) respectively) paralleled by a rapid increase in nitric oxide. Inhibition of Src kinase decreased eNOS and Akt phosphorylation, in contrast to a lack of any effect on insulin mediated activation of the eNOS-Akt, suggesting that alogliptin mediates vasodilation through Src kinase mediated effects on eNOS-Akt. DPP-4 inhibition by alogliptin mediates rapid vascular relaxation via GLP-1 independent, Src-Akt-eNOS mediated NO release and the activation of vascular potassium channels.
authors.affiliation: Davis Heart & Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: Zubair
authors.initials: Z
authors.lastname: Shah
authors.forename: Colleen
authors.initials: C
authors.lastname: Pineda
authors.forename: Thomas
authors.initials: T
authors.lastname: Kampfrath
authors.forename: Andrei
authors.initials: A
authors.lastname: Maiseyeu
authors.forename: Zhekang
authors.initials: Z
authors.lastname: Ying
authors.forename: Ira
authors.initials: I
authors.lastname: Racoma
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Deiuliis
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Xu
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Sun
authors.forename: Susan
authors.initials: S
authors.lastname: Moffatt-Bruce
authors.forename: Frederick
authors.initials: F
authors.lastname: Villamena
authors.forename: Sanjay
authors.initials: S
authors.lastname: Rajagopalan
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D001685:Biological Factors / Q000378:metabolism; D002478:Cells, Cultured; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D015221:Potassium Channels / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001685:Biological Factors; D054873:Dipeptidyl-Peptidase IV Inhibitors; D010880:Piperidines; D015221:Potassium Channels; C067410:endothelium-dependent hyperpolarization factor; D009569:Nitric Oxide; D014498:Uracil; D052216:Glucagon-Like Peptide 1; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse; C520853:alogliptin